THE VETERINARIAN'S CHOICE. Introducing new MILPRO from Virbac. Compendium clinical Trials Go pro. Go MILPRO..
milbemycin/praziquantel Content INTRODUCTION 05 I. EFFICACY STUDIES IN CATS 06 I.I. Efficacy study: Dose confirmation against immature and adult Dipylidium caninum in experimentally infected cats. 08 I.II. Efficacy study: Dose confirmation against adult Toxocara cati in experimentally infected cats. 09 I.III. Efficacy study: Dose confirmation against adult Ancylostoma tubaeforme in experimentally infected cats. 10 II. EFFICACY STUDIES IN DOGS 12 II.I. Efficacy study: Dose confirmation against Dipylidium caninum in naturally infected dogs. 14 II.II. Efficacy study: Dose confirmation against Ancylostoma caninum in naturally infected dogs. 15 II.III. Efficacy study: Dose confirmation against Toxocara canis in naturally infected dogs. 16 II.IV. Efficacy study: Dose confirmation against Trichuris vulpis in naturally infected dogs. 17 II.V. Efficacy study: Dose confirmation against adult Echinococcus multilocularis in experimentally infected dogs. 18 III. TAS (TARGETED ANIMAL SAFETY) STUDY IN CATS 20 IV. PALATABILITY STUDY IN DOGS 24 V. COMPARATIVE PALATABILITY STUDY IN CATS 28
Introduction Milpro is a broad-spectrum dewormer intended for oral administration for the treatment of mixed infections with roundworms, hookworms, whipworms and tapeworms, reduction of infection with lungworms and the prevention of heartworm disease in dogs. The product is administered in cats for the treatment of mixed infections with immature and adult cestodes and nematodes and for prevention of heartworm disease if concomitant treatment against cestodes is indicated. The product has two active substances, Milbemycin Oxime and Praziquantel, in a solid dosage form: a tablet with palatable coating for use in both dogs and cats. The product was developed as a generic medicinal product of Milbemax Tablets currently marketed by Novartis. Particular attention was given to obtaining the same active ingredient content and the same pharmaceutical form as the reference product. However, from a regulatory point of view Milpro is a hybrid application; this implies that original studies in both species were conducted: -original effi cacy studies -original tolerance studies -original palatability studies -bioequivalence studies Registration Dossier Original product Hybrid product Generic product Part I Summary Summary Summary Part II Quality Quality Quality Part III Safety (environment, user, target species) Tolerance in Target Species (TAS) + Bioequivalence (PK) None Table 01: Differences between regulatory procedures (original product, hybrid product and generic product) Part IV Efficacy studies Efficacy studies + Bioequivalence (PK) Bioequivalence only 05
milbemycin/praziquantel I. Efficacy studies in cats
Compendium Clinical Trials milbemycin/praziquantel I.I. Efficacy study: Dose confirmation against immature and adult Dipylidium caninum in experimentally infected cats. The aim of this study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against D. caninum in experimentally infected cats. The study was a single-centre, randomised, parallel-arm, blinded, negative controlled dose confi rmation study. Materials and Methods: Number of cats Average Body Weight (BW) Day of experimental infection Day of treatment Estimated stage of D. caninum Euthanasia and Necropsy at D35 Group 1 10 1.99 kg** D-3 and D0 None All stages* Group 2 10 1.97 kg** D-3 and D0 D0+5 Immature* Table 02: Materials and methods in the study against D. caninum Group 3 10 1.97 kg** D-3 and D0 D0+25 Adults* * Estimated prepatent period in D.canimum is 16 to 21 days. Thirty cats were infested with D. caninum infected fl eas on Day -3 and orally infected with D. caninum (in infected fl eas) on Day 0. ** Body weight on Day +4 of the included cats ranged between 0.42 and 3.79 kg (average 1.98 kg, n = 30). The cats were cross-bred and of both sexes. All the cats were less than 1 year old on the day of infection. Results of the study: Dipylidium caninum adequately infected cats in the control group as determined by the numbers of worms recovered at necropsy. The difference between treated and control groups with regard to the numbers of D. caninum scoleces recovered at necropsy was statistically signifi cant (p <0.0001). Based on worm recovery at necropsy, the effi cacy of treatment tablets was 100.00 % against D. caninum adult and immature stages. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The cats tolerated the experimental treatments well and no treatment-related adverse events were recorded. Oral treatment Number of infected cats Number of worms found at necropsy in infected animals Efficacy of treatment Group 1 None 8 out of 10 1 to 63 (geometric mean 8.80) Not applicable Group 2 (acc. to BW) 0 out of 10 0 100.00% Table 03: Results of study against D. caninum Group 3 (acc. to BW) 0 out of 10 0 100.00% 08
I. Efficacy studies in cats I.II. Efficacy study: Dose confirmation against adult Toxocara cati in experimentally infected cats. The aim of this study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against mature T. cati in experimentally infected cats. The study was a single-centre, randomised, parallel-arm, blinded, negative controlled dose confi rmation study. Materials and Methods: Number of cats Average Body Weight (BW) Day of experimental infection Day of treatment Estimated stage of T. cati Euthanasia and Necropsy at D7 Group C 8 1.99 kg D-60 None All stages Table 04: Materials and methods in the study against T. cati Group M 8 1.97 kg D-60 D0 Adults stages The cats were acclimatised to study conditions for seven days, from Day -67 to Day -61. On Day -60, 18 days after they had been dewormed, all cats were inoculated with infective (larvated) eggs of T. cati. The days of treatment for group M had been selected to target adult stages (60 days post-infection). The cats were observed for general health from Day -67 to Day +7 and underwent clinical examination during acclimatisation. The cats were randomly allocated to study groups. Both sexes were represented in each treatment group. The cats were less than 1 year old at the time of experimental infection. Following the administration of Milpro all the cats were observed for possible adverse events. At the end of the animal phase (Day +7) the cats were euthanised and the gastrointestinal helminths were recovered during necropsy. Worms were identifi ed and counted. Effi cacy calculations were based on the worms recovered at necropsy in the treatment groups compared to the control group. Results of the study: Based on worm recovery at necropsy, the effi cacy of treatment tablets was 100.00 % against T. cati adult stages. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The cats tolerated the experimental treatments well and no treatment-related adverse events were recorded. Table 05: Results of study against T. cati Treatment Number of infected cats Group C None 8 out of 8 Number of worms found at necropsy in infected animals 5 to 107 worms (mean 16.70) Targeted stage of worms Not applicable Efficacy of treatment Not applicable Group M (acc. to BW) 0 out of 8 0 Mature stages 100.00% 09
Compendium Clinical Trials milbemycin/praziquantel I.III. Efficacy study: Dose confirmation against adult Ancylostoma tubaeforme in experimentally infected cats. The aim of the study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against A. tubaeforme in experimentally infected cats. The study was a singlecentre, randomised, parallel-arm, blinded, negative controlled dose confi rmation study. Materials and Methods: Number of cats Average Body Weight (BW) Day of experimental infection Day of treatment Estimated stage of A. tubaeforme Euthanasia and Necropsy at D+7 Group 1 9 1.46 kg** D-28 None Adult stages* Table 06: Materials and methods in the study against A. tubaeforme Group 2 9 1.50 kg** D-28 D0 Adult stages* *Approximately 28 days (start of acclimatisation was dependent on the rate of parasite development as observed through egg shedding) before the start of the animal phase, 32 cats were infected orally with ~ 300 Ancylostoma tubaeforme larvae. Only positive cats were enrolled at D-7 (i.e. 18 cats in total) in the animal phase. On three days during acclimatisation, quantitative A. tubaeforme egg counts were conducted (cats with a faecal egg count of at least 200 A. tubaeforme eggs per gram of faeces (epg) were included). A mean pre-treatment egg-value was calculated for each cat and was used to rank the cats for randomisation. The cats were randomly allocated to two study groups each with 9 cats. Both sexes were represented in each group. At the end of the animal phase (Day+7) the cats were euthanised and the gastrointestinal helminths were recovered during necropsy. Worms were preserved prior to being identifi ed and counted at a later date. ** Body weight on Day -7 of the included cats ranged between 0.68 and 2.84 kg (average 1.48 kg, n = 18). The cats included were of both sexes and, at least 8 weeks old. Results of the study: Ancylostoma tubaeforme adequately infected cats in the control group as determined by the numbers of worms recovered at necropsy. The difference between treated and control groups with regard to the numbers of A. tubaeforme recovered at necropsy was statistically signifi cant (p = 0.001). Based on worm recovery at necropsy, the effi cacy of treatment tablets was 98.2% (based on geometric mean) against A. tubaeforme adult stages. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The cats tolerated the experimental treatments well and no adverse events were recorded. Day of treatment Number of cats from which worms were recovered Number of worms in cats at necropsy Efficacy of treatment Group 1 None 9 out of 9 60 to 274 worms (geometric mean 149.30) Not applicable Table 07: Results of study against A. tubaeforme Group 2 D0 4 out of 9 0 to 107 worms (geometric mean 2.64) 98.20% Additional data: As expected (based on arithmetic mean faecal egg counts) a drastic reduction in egg count was observed in the Milpro -treated group 2 (6256.8 versus 600.0 eggs per gram of faeces). The count for the untreated control group remained virtually unchanged (5967.9 versus 5044.4 eggs per gram of faeces). Faecal egg count results were considered a secondary, supportive criterion and no effi cacy calculations based on egg count were calculated. 10
I. Efficacy studies in cats 11
milbemycin/praziquantel II. Efficacy studies in dogs
Compendium Clinical Trials milbemycin/praziquantel II.I. Efficacy study: Dose confirmation against Dipylidium caninum in naturally infected dogs. The objective of this study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against D. caninum in naturally infected dogs. The study was a singlecentre, randomized, parallel-arm, blinded, negative controlled dose confi rmation study. Materials and Methods: Number of dogs Average Body Weight (BW) Milpro oral Day of diagnosis Estimated stage of D. caninum Euthanasia and Necropsy at D10 Group 1 10 11.28 kg None D-7 to D-1 All stages Table 08: Materials and methods in the study against D. caninum Group 2 10 9.96 kg (acc. to BW) D-7 to D-1 All stages In total 30 dogs were acclimatised to study conditions for seven days, from Day -7 to Day -1. During acclimatisation dogs had to be diagnosed at least once as infected with D. caninum. Faeces were screened daily to detect expelled proglottids. Once a dog had been diagnosed positive during acclimatisation, no further faecal examinations were conducted for that dog. On Day -1 only twenty-one dogs were found to be positive for infection with D. caninum of which twenty were included in the study. The 20 dogs included were randomly allocated to two study groups, balanced with regard to gender and body weight. All the dogs were estimated to be older than 4 months. Milpro tablets were administered once only on Day 0 to dogs in group 2. Dogs in group 1 remained untreated to serve as a negative control group. Following the administration of Milpro all the dogs were observed for possible adverse events. At the end of the animal phase (Day +10) the dogs were euthanised and the gastrointestinal helminths were recovered during necropsy. Results of the study: Dipylidium caninum adequately infected dogs in the control group as determined by the numbers of scoleces recovered at necropsy. The difference between treated and control groups with regard to the numbers of D. caninum recovered at necropsy was statistically signifi cant (ANOVA, p=0.0002). Based on worm recovery at necropsy, the efficacy of treatment tablets was 100.00 % against D. caninum. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The dogs tolerated the experimental treatments well and no adverse events were recorded. Day of treatment Number of infected dogs Number of worms found at necropsy in infected animals Efficacy of treatment Table 09: Results of study against D. caninum Group 1 None 9 out of 10 0 to 129 worms (geometric mean 8.20) Not applicable Group 2 D0 0 out of 10 0 100.00% 14
II. Efficacy studies in dogs II.II. Efficacy study: Dose confirmation against Ancylostoma caninum in naturally infected dogs. The aim of the study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against A. caninum in naturally infected dogs. The study was a single-centre, randomised, blinded, parallel-arm, negative controlled dose confi rmation study. Materials and Methods: Number of dogs Average Body Weight (BW) Milpro oral Day of diagnosis Estimated stage of A. caninum Euthanasia and Necropsy at D7 Group 1 10 6.85 kg None D-4 to D-2 Adult stages Table 10: Materials and methods in the study against A. caninum Group 2 10 7.98 kg (acc. to BW) D-4 to D-2 Adult stages Twenty-four dogs were acclimatised for study purposes from Day -7. On Day -1 only 20 dogs, diagnosed as infected with A. caninum, were included in the study and allocated to two study groups, each consisting of ten animals. Both sexes were represented in each group. The animals were estimated to be at least 8 weeks of age; approximately half of the animals were less than 6 months of age. Milpro was administered to group 2 orally, once only, on Day 0. Following the administration of Milpro all the dogs were observed for possible adverse events. At the end of the animal phase (Day +7) the dogs were euthanised and gastrointestinal helminths were recovered during necropsy. Worms were identifi ed and counted. Effi cacy calculations were based on the worms recovered at necropsy in the treatment group (Group 2) compared to the control group (Group 1). Results of the study: Ancylostoma caninum adequately infected dogs in the control group as determined by the numbers of worms recovered at necropsy. The difference between treated and control groups with regard to the numbers of A. caninum recovered at necropsy was statistically signifi cant (p <0.0001). Based on worm recovery at necropsy, the effi cacy of treatment tablets was 94.5% (based on geometric mean) against A. caninum. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The dogs tolerated the experimental treatment well. Day of treatment Number of worms in dogs at necropsy Efficacy of treatment Group 1 None 4 to 235 worms (geometric mean 25.90) Not applicable Table 11: Results of study against A. caninum Group 2 D0 0 to 11 worms (geometric mean 1.42) 94.50% 15
Compendium Clinical Trials milbemycin/praziquantel II.III. Efficacy study: Dose confirmation against Toxocara canis in naturally infected dogs. The aim of the study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against T. canis in naturally infected dogs. The study was a single-centre, randomised, blinded, parallel-arm, negative controlled dose confi rmation study. Materials and Methods: Number of dogs Average Body Weight (BW) Milpro oral Day of diagnosis Estimated stage of T. canis Euthanasia and Necropsy at D7 Group 1 9 3.17 kg None D-4 to D-2 All stages Table 12: Materials and methods in the study against T. canis Group 2 9 3.89 kg (acc. to BW) D-4 to D-2 All stages Twenty dogs diagnosed as infected with Toxocara canis were acclimatised from Day -7. The inclusion criterion was 300 or more T. canis eggs per gram of faeces on at least one occasion during acclimatisation. Eighteen dogs were included in the study and allocated to two study groups, each consisting of nine animals. Both sexes were represented in each group. All dogs were estimated to be younger than 6 months. Milpro (IVP) was administered to group 2 orally, once only, on Day 0. Following the administration of Milpro all the dogs were observed for possible adverse events. Total faeces were collected daily from post-treatment on Day 0 up to Day +7 and were preserved for later recovery of T. canis worms expelled in the faeces. At the end of the animal phase (Day +7) the dogs were euthanised and the gastrointestinal helminths were recovered during necropsy. Worms were identifi ed and counted. Primary effi cacy calculations were based on the worms recovered at necropsy in the treatment group (2) compared to the control group (1). A critical effi cacy evaluation was based on the number of worms expelled in the faeces and the numbers remaining at necropsy. Results of the study: Adult Toxocara canis adequately infected dogs in the control group as determined by the numbers of worms recovered at necropsy. The difference between treated and control groups with regard to the numbers of adult T. canis recovered at necropsy was statistically signifi cant (ANOVA p <0.0001). Based on worm recovery at necropsy, the effi cacy of treatment tablets was 99.6% against adult T.canis. This was higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. A critical test was also applied, based on the numbers of T. canis worms expelled in the faeces. In the control group 4.20% of worms were expelled in the faeces, whereas 99.07% of worms were expelled in the faeces of dogs in the treated group. Data from post-treatment T. canis egg counts supported the other effi cacy results. In the control group the Day +6 egg counts were similar to the pre-treatment counts (2970.4 and 2750.7 respectively), whereas no T. canis eggs were present in the faeces of dogs in the treated group on Day +6. All dogs tolerated the Milpro well, no side effects were noticed. Day of treatment Number of dogs from which worms were recovered Number of adult worms in dogs at necropsy Efficacy of treatment against adult worms Expelled T. canis worms in faeces Group 1 None 8 out of 9 0 to 55 worms (geometric mean 16.40) Not applicable 4.2% (n=11) Table 13: Results of study against T. canis Group 2 D0 1 out of 9 1 worm (geometric mean 0.1) 99.60% 99.07% (n=106) 16
II. Efficacy studies in dogs II.IV. Efficacy study: Dose confirmation against Trichuris vulpis in naturally infected dogs. The objective of this study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against T. vulpis in naturally infected dogs. The study was a singlecentre, randomised, blinded, parallel-arm, negative controlled dose confi rmation study. Materials and Methods: Number of dogs Average Body Weight (BW) Milpro oral Day of infection control Estimated stage of T. vulpis Euthanasia and Necropsy at D7 Group 1 10 12.30 kg None D-4 to D-2 All stages Table 14: Materials and methods in the study against T. vulpis Group 2 10 12.05 kg (acc. to BW) D-4 to D-2 All stages Twenty dogs were acclimatised from Day -7 to Day -1. On three occasions (Days -4 to -2) the twenty dogs were all diagnosed as infected with Trichuris vulpis (T. vulpis) by faecal egg counts performed for all animals individually. The inclusion criterion was 60 or more T. vulpis eggs per gram of faeces on at least one occasion. Following this, dogs were allocated to two study groups each consisting of ten animals. Both sexes were represented in each treatment group. All dogs were estimated to be older than 6 months. On Day 0 Milpro tablets were orally administered once only to the animals in group 2 according body weight. Group 1 served as a negative control group in which the animals remained untreated. Following the administration of Milpro tablets all the dogs were observed for possible adverse events. At the end of the animal phase (Day +7) the dogs were euthanised and the gastrointestinal helminths were recovered during necropsy. Worms were identifi ed and counted. Effi cacy calculations were based on the worms recovered at necropsy in the treatment group compared to the control group. Results of the study: Adult Trichuris vulpis adequately infected dogs in the control group as determined by the numbers of worms recovered at necropsy. The difference between treated and control groups with regard to the numbers of adult T. vulpis recovered at necropsy was statistically signifi cant (ANOVA p < 0.0001). Based on worm recovery at necropsy, the effi cacy of treatment was 97.0% against adult T. vulpis. This is higher than the 90% effectiveness stipulated by the protocol to demonstrate effi cacy against this parasite. The dogs tolerated the experimental treatments well. No adverse events occurred. Day of treatment Number of dogs from which worms were recovered Number of adult worms in dogs at necropsy Efficacy of treatment against adult worms Efficacy of treatment against immature adult worms Group 1 None 10 out of 10 35 to 227 worms (geometric mean 75.20) Not applicable Not applicable Table 15: Results of study against T. vulpis Group 2 D0 6 out of 10 0 to 50 worms (geometric mean 2.5) 97.00% 96.70% 17
Compendium Clinical Trials milbemycin/praziquantel II.V. Efficacy study: Dose confirmation against adult Echinococcus multilocularis in experimentally infected dogs. The aim of the study was to confi rm the effi cacy of an orally administered anthelmintic formulation, Milpro tablets, against Echinococcus multilocularis in experimentally infected dogs. The study was a single-centre, randomised, parallel-arm, blinded, negative controlled dose confi rmation study. Materials and Methods: Number of dogs Average Body Weight (BW) Milpro oral Day of infection Estimated stage of E. multilocularis Euthanasia and Necropsy at D+5 Group 1 10 11.05 kg None D-18 Adults Table 16: Materials and methods in the study against E. multilocularis Group 2 10 12.24 kg (acc. to BW) D-18 Adults In preparation for the study, 26 dogs, at least 8 weeks of age, were dewormed more than 14 days before experimental infection. Following acclimatisation only twenty dogs were orally infected with protoscoleces from a strain of E. multilocularis on Day -18 in accordance with VICH GL19 guidelines. The dogs were infected with approximately 15 000 E. multilocularis protoscoleces, from a European isolate less than 10-years old. On Day -1 the dogs were randomly assigned to two study groups of 10 dogs each. Both sexes were represented in each treatment group. On Day 0 all dogs assigned to group 2 were orally treated. The dogs in group 1 remained untreated. Following the administration of Milpro the dogs were observed for possible adverse events. At the end of the animal phase (Day +5) the dogs were euthanised and the gastrointestinal helminths were recovered during necropsy. Worms were identifi ed and counted. Effi cacy calculations were based on the worms recovered at necropsy in the treatment group compared to the control group. Results of the study: In the control group E. multilocularis scoleces were recovered from nine of the ten dogs at necropsy. Seven of the dogs had more than 230 worms so the infection was considered adequate for further analysis. In the treated group none of the animals were infected with E. multilocularis at necropsy. The control and treatment groups differed signifi cantly with regard to the number of worms recovered at necropsy (p=0.0001). The effi cacy of treatment with the orally administered anthelmintic formulation, Milpro tablets, was 100% against E. multilocularis in experimentally infected dogs. The dogs tolerated the experimental treatments well and no adverse events occurred during the study. Day of treatment Number of dogs from which worms were recovered Number of scoleces in dogs at necropsy Efficacy of treatment Table 17: Results of study against E. multilocularis Group 1 None 9 out of 10 0 to 990 worms (geometric mean 91.00) Not applicable Group 2 D0 0 out of 10 0 worms 100.00% 18
II. Efficacy studies in dogs 19
milbemycin/praziquantel III. TAS (targeted animal safety) study in cats
Compendium Clinical Trials The objective of this study was to evaluate the tolerance of the Milpro tablets following repeated oral administration (tablet) to European kittens at one, three or fi ve times the expected normal therapeutic dose (ND) and for a duration which exceeded the therapeutic indication for veterinary use. Materials and Methods: The animals were treated on three occasions at 2-week intervals, followed by a 2-week observation period as shown in the table below: Day 1 product Observation (D1 to D14) Day 15 product Observation (D15 to D28) Day 29 product Observation (D29 to D43) Group 1 control 8 cats None None None Group 2 8 cats ND* ND ND Group 3 8 cats 3 times ND 3 times ND 3 times ND Table 18: Product administration in each group Group 4 8 cats 5 times ND 5 times ND 5 times ND ND* normal dosage (i.e. depending on the body weight of the kitten, the practical dose is half a tablet (for a kitten weighing between 0.5 and 1 kg) or one tablet (for a kitten weighing between 1 and 2 kg). Therefore, the minimum recommended dose is 2 mg of Milbemycin oxime and 5 mg of Praziquantel per kg.) The animals were checked daily for mortality and abnormal clinical signs. A detailed physical examination was performed once during the pre-treatment period and then weekly, including 1 and 4 hours after each treatment. Rectal temperature was recorded once during the pre-treatment period, on the day before each treatment and at the end of the study. Body weight was recorded three times during the pre-treatment period (including on day -1), and then once a week. The amount of food consumed by each animal was estimated on the days of treatment (just before treatment and at the end of the day). Haematology and blood biochemistry investigations were performed during the pre-test, on the days after each treatment, once between the fi rst and second treatment and at the end of the study. Urinary investigations were carried out during the pre-test and on the day after the last treatment. On completion of the observation period, the animals were returned to stock. 22
III. TAS study in cats Results of the study: No mortality occurred during the study. Some very mild clinical signs, including hypoactivity, ventral recumbency and/or sedation, tremors during handling, ptyalism, were observed at 5 times ND in some animals after the second and third administrations. These observations, which generally appeared 4 hours after treatment, were often still present at the end of the day. Nevertheless, all clinical signs disappeared spontaneously within 24 hours after treatment. No clinical signs relating to the Milpro treatment were observed in animals treated at ND or 3 times ND during any of the treatment and observation periods. No Milpro -related effects on rectal temperature, body weight or food consumption (on the days of treatment) were noted. In laboratory investigations (haematology, blood biochemistry, serum amyloid A levels and urinalysis) no test item-related changes were noted. Conclusion of the study: Test item-related effects were confi ned to mild systemic signs at the highest dose level (i.e. 5 times ND) after the second and third treatments. The symptoms disappeared spontaneously within 24 hours after treatment. Therefore, no concerns for safety were recorded for the animals treated at ND or 3 times ND. 23
milbemycin/praziquantel IV. Palatability study in dogs
Compendium Clinical Trials The aim of this study was to evaluate the palatability of two presentations of Milpro tablets, containing Milbemycine Oxime and Praziquantel, for dogs and for puppies. Materials and Methods: The animals included in the study were all healthy; 15 adult (male and female) beagle dogs and 15 (male and female) beagle puppies, as presented in the table below: Female Male Total Puppy 9 6 15 Average weight (kg) 4.2 +/- 1.09 5.0 +/- 0.84 4.5 +/- 1.06 Minimum weight (kg) 2.7 3.9 2.7 Maximum weight (kg) 5.6 6.3 6.3 Average age (week) 14.23 +/- 0.70 13.89 +/- 0.37 14.09 +/- 0.60 Minimum age (week) 12.96 13.25 12.96 Maximum age (week) 15.24 14.39 15.24 Female Male Total Adult 6 9 15 Average weight (kg) 12.8 +/- 1.47 14.6 +/- 0.74 13.9 +/- 1.39 Minimum weight (kg) 11.3 13.4 11.3 Maximum weight (kg) 15.4 15.5 15.5 Average age (week) 2.97 +/- 0.78 2.34 +/- 0.12 2.59+/- 0.57 Minimum age (week) 1.86 2.25 1.86 Table 19: Animal characteristics Maximum age (week) 3.78 2.65 3.78 Dogs were fed with dry food provided ad libitum, which was withdrawn during the test and replaced 4 hours after the palatability test. The tablets were handled with a specifi c clamp. The product was placed on the ground in front of the animal. The behavior of the dog in regard to the tablet was noted. The events that were recorded were whether it was picked up or not, and its consumption (full, partial or none). If a dog showed no interest in the tablet because of not fi nding it, the technical team presented the tablet again. The maximum presentation time was one minute. 26
IV. Palatability study in dogs Results of the study: Milpro tablets demonstrated excellent palatability. In adult dogs and puppies the rate of prehension was 100%. The rate of spontaneous total consumption for puppies was 100% (15 dogs) and the rate of spontaneous total consumption in adult dogs was 87% (13 dogs), with partial consumption for only 13% (2 dogs). No refusals were noted for Milpro in this study. 100% 90% 2 dogs 80% 70% Proportion of dogs 60% 50% 40% 30% 13 dogs 15 dogs Spontaneous partial consumption Spontaneous total consumption 20% 10% Figure 20: Palatability study in dogs, Milpro tablet consumption 0% Milpro dog Milpro puppy Different presentations 27
milbemycin/praziquantel V. Comparative palatability study in cats
Compendium Clinical Trials The aim of this study was to evaluate the palatability of two presentations of Milpro tablets containing Milbemycine Oxime and Praziquantel for cats and for kittens in comparison to the reference product Milbemax. Materials and Methods: Two distinct studies each with 20 healthy cats or kittens were conducted (40 animals in total); only one type of tablet was tested each day (either Milpro or Milbemax ). Each product was presented at the recommended posology, ie all kittens received an entire kitten tablet, all adult cat weighting less than 4 kg of BW received half of an adult tablet and all adult cat weighting more than 4 kg of BW received an entire adult tablet. Each time, the product was presented to each animal before feeding in the morning, food was administered one hour later. The tablets were presented in the bowl for 2 minutes, in the case of non-intake it was additionally presented in the hand for 30 seconds. Prehension and total consumption were recorded. For the study with adult cats the weight of the animals ranged from 3.35 to 5.23 kg, the age was between 9 months and 4 years and both sexes were present. For the study with kittens the weight of the animals ranged from 1.31 to 1.96 kg, the age was between 4 and 6 months and both sexes were present. 30
V. Comparative palatability study in cats Results of the study: Milpro and Milbemax tablets demonstrated good palatability in cats and kittens with an advantage for Milpro tablets. In adult cats the rate of prehension was 100% for Milpro and 95% for Milbemax. In kittens the rate of prehension was for 45% Milpro and 30% for Milbemax. The rate of spontaneous total consumption for Milpro in kittens was 45% and the rate of spontaneous total consumption in adult cats was 40%. The rate of spontaneous total consumption for Milbemax in kittens was rather low, 20%, with the rate of spontaneous total consumption in adult cats also lower than, 45%. These data are presented in the table below: 100% 90% 80% 70% Milpro for cats Existing product 100% 95% Milpro for cats Proportion of cats 60% 50% 40% 30% Milpro for cats Existing product 40% 35% Spontaneous prehension Total consumption 20% 10% Figure 21: The palatability of Milpro for cats is equivalent to that of the existing milbemycin/praziquantel product 0% (n=20) Tablets for adult cats (n=20) 45% 40% 35% Proportion of cats 30% 25% 20% 15% 9 cats Spontaneous total consumption 10% 4 cats Figure 22: Comparative palatability study in kittens: Milpro and Milbemax tablet consumption 5% 0% Milpro kittens Milbemax kittens Tablets for small cats and kittens 31
milbemycin/praziquantel Passionate about animal health